This invention is directed to compounds with antibacterial activity, processes for making the compounds and intermediates used in the processes, compositions containing the compounds, and methods for prophylaxis or treatment of bacterial infections using the compounds.
Because the effectiveness of many drugs currently available for prophylaxis or treatment of bacterial infections is being compromised by the emergence of drug-resistant bacteria, novel antibacterial compounds would be beneficial for their therapeutic value and their contribution to the antibacterial arts.
A first embodiment of this invention, therefore, is directed to compounds, and salts, prodrugs, and salts of prodrugs thereof, having antibacterial activity, the compounds having formula (I) 
in which
two of A1, B1, D1, and E1 are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, xe2x80x94CN, xe2x80x94OH, xe2x80x94SH, xe2x80x94C(O)H, xe2x80x94C(O)R1, xe2x80x94C(O)OH, xe2x80x94C(O)OR1, xe2x80x94C(O)NR2R3, or alkyl substituted by one, two, or three substituents independently selected from the group consisting of xe2x80x94CN, xe2x80x94OH, xe2x80x94SH, halo, aryl, heteroaryl, heterocyclyl, xe2x80x94OR1, xe2x80x94SR1, xe2x80x94C(O)H, xe2x80x94C(O)R1, xe2x80x94C(O)OH, xe2x80x94C(O)OR1, xe2x80x94CHxe2x95x90Nxe2x80x94OR1, xe2x80x94OC(O)R1, xe2x80x94OC(O)OR1, xe2x80x94C(O)NR2R3, xe2x80x94OC(O)NR2R3, xe2x80x94NR2R3, xe2x80x94N(R4)C(O)H, xe2x80x94N(R4)C(O)R1, xe2x80x94N(R4)C(O)NR2R3, xe2x80x94N(R4)SO2R1, xe2x80x94OR1, xe2x80x94SR1, xe2x80x94S(O)R1, xe2x80x94SO2R1, and xe2x80x94SO2NR2R3, and the remainder are hydrogen; or
A1 and D1, A1 and E1, B1 and D1, or B1 and D1 together are one- to five-membered alkylene or two to five-membered heteroalkylene, and the remainder are hydrogen; or
A1 and B1 together are one- to seven-membered alkylene or two- to seven-membered heteroalkylene, and D1 and E1 are hydrogen; or
D1 and E1 together are one- to seven-membered alkylene or two- to seven-membered heteroalkylene, and A1 and B1 are hydrogen;
X1 is hydrogen or fluoride;
M1 is (E)-CHxe2x95x90CH, (Z)-CHxe2x95x90CH, or Cxe2x89xa1C;
Y1 is arylene or heteroarylene;
L1 is drawn from left to right and is alkylene, alkenylene, alkynylene, CHxe2x95x90Nxe2x80x94Oxe2x80x94CH2-(alkenylene), CH2N(R5), CH2N(R5)(CH2)m, C(O)N(R5), N(R5)C(O)N(R6), CHxe2x95x90Nxe2x80x94N(R5), CHxe2x95x90Nxe2x80x94N(R5)C(O), O, CHxe2x95x90Nxe2x80x94O, CHxe2x95x90Nxe2x80x94Oxe2x80x94(CH2)m, C(O)N(R5)(CH2)m, or CHxe2x95x90Nxe2x80x94O(CH2)nxe2x80x94O,
in which m is one, two, three, or four, and n is two, three, or four;
W1 is hydrogen aryl, heteroaryl, or heterocyclyl;
R1 is alkyl, aryl, heteroaryl, or heterocyclyl;
R2 and R3 are independently hydrogen or alkyl; or
R2 and R3 together are 3- to 7-membered alkylene or 3-to 7-membered heteroalkylene;
R4 is hydrogen or alkyl;
R5 and R6 are independently hydrogen or alkyl; and
RA is hydrogen or RP in which RP is a hydroxyl protecting moiety;
in which, for the foregoing,
each aryl, arylene, heteroaryl, heteroarylene, heterocyclyl, and heterocycloalkylene is unsubstituted or substituted by one, two, three, four, or five substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, halo, xe2x80x94CN, xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, xe2x80x94NO2, xe2x95x90O, xe2x80x94CF3, xe2x80x94CH2CF3, xe2x80x94CF2CF3, xe2x80x94OCF3, xe2x80x94OCH2CF3, xe2x80x94OCF2CF3, xe2x80x94OR30, xe2x80x94SR30, xe2x80x94S(O)R35, xe2x80x94SO2R35, xe2x80x94C(O)H, xe2x80x94C(O)R35, xe2x80x94C(O)OH, xe2x80x94C(O)OR35, xe2x80x94NH(R35), xe2x80x94N(R35)(R36), xe2x80x94C(O)NH2, xe2x80x94C(O)NH(R35), xe2x80x94C(O)N(R35)(R36), xe2x80x94OC(O)R35, xe2x80x94OC(O)OR35, xe2x80x94OC(O)NH2, xe2x80x94OC(O)NH(R35), xe2x80x94OC(O)N(R35)(R36), xe2x80x94NHC(O)H, xe2x80x94NHC(O)R35, xe2x80x94NHC(O)OR35, xe2x80x94NHC(O)NH2, xe2x80x94NHC(O)NH(R35), xe2x80x94NHC(O)N(R35)(R36), xe2x80x94SO2NH2, xe2x80x94SO2NH(R35), xe2x80x94SO2N(R35)(R36), R40, and alkyl substituted with one or two substituents independently selected from the group consisting of halo, xe2x80x94CN, xe2x80x94OH, xe2x80x94SH, xe2x95x90O, xe2x80x94OR30, xe2x80x94SR30, xe2x80x94C(O)OH, xe2x80x94C(O)OR35, xe2x80x94NH2, xe2x80x94NH(R35), xe2x80x94N(R35)(R36), xe2x80x94C(O)NH2, xe2x80x94C(O)NH(R35), xe2x80x94C(O)N(R35)(R36), xe2x80x94OC(O)R35, xe2x80x94OC(O)NH2, xe2x80x94OC(O)NH(R35), xe2x80x94OC(O)N(R35)(R36), xe2x80x94SO2NH2, xe2x80x94SO2NH(R35), xe2x80x94SO2N(R35)(R36) and R40;
R30 is alkyl or alkyl substituted with a substituent selected from the group consisting of halo and xe2x80x94OR45;
R35 and R36 are independently selected alkyl;
R40 is phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrrolidinyl, inidazolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of which is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, halo, xe2x80x94CN, xe2x80x94OH, xe2x80x94SH, xe2x80x94NO2, xe2x95x90O, xe2x80x94CF3, xe2x80x94CH2CF3, xe2x80x94CF2CF3, xe2x80x94OCF3, xe2x80x94OCH2CF3, xe2x80x94OCF2CF3, xe2x80x94OR45, xe2x80x94SR45, xe2x80x94S(O)R50, xe2x80x94SO2R50, xe2x80x94C(O)H, xe2x80x94C(O)R50, xe2x80x94C(O)OH, xe2x80x94C(O)OR50, xe2x80x94NH2, xe2x80x94NH(R50), xe2x80x94N(R50)(R51), xe2x80x94C(O)NH2, xe2x80x94C(O)NH(R50), xe2x80x94C(O)N(R50)(R51), xe2x80x94OC(O)R50, xe2x80x94OC(O)OR50, xe2x80x94OC(O)NH2, xe2x80x94OC(O)NH(R50), xe2x80x94OC(O)N(R50)(R51), xe2x80x94NHC(O)H, xe2x80x94NHC(O)R50, xe2x80x94NHC(O)OR50, xe2x80x94NHC(O)NH2, xe2x80x94NHC(O)NH(R50), xe2x80x94NHC(O)N(R50)(R51), xe2x80x94SO2NH2, SO2NH(R50), and xe2x80x94SO2N(R50)(R51);
R45 is alkyl; and
R50 and R51 are independently selected alkyl.
A second embodiment of this invention is directed to processes for making the compounds of the first embodiment.
A third embodiment of this invention is directed to intermediates which are useful in the second embodiment.
A fourth embodiment of this invention is directed to compositions comprising a therapeutically effective amount of a compound of the first embodiment.
A fifth embodiment of this invention is directed to methods for prophylaxis or treatment of bacterial infections in a fish or a mammal comprising administering thereto a therapeutically effective amount of a compound of the first embodiment.
In a preferred fifth embodiment of this invention, the beneficiary of prophylaxis or treatment of bacterial infections is a mammal.
In a more preferred fifth embodiment of this invention, the beneficiary of prophylaxis or treatment of bacterial infections is a human.